: The effect of innate cellular activation on HIV transmission efficiency, absent inflammation of the genital mucosa associated with active co-infections, remains unknown. Although some early attempts at answering this question have been tried, recent results now strongly justify revisiting this unresolved problem as new data support the premise that a specific arm of the innate activation response may be a significant factor in affecting HIV transmission in absence of co-infections. We will collect both direct and indirect correlative data to test the hypothesis that plasmacytoid dendritic cells (pDC) recruitment and activation into the cervicovaginal compartment by HIV-1 particles or infected cells not resulting in productive HIV-1 infection (low dose, defective particles) will result in both innate and Treg adaptive mechanisms able to lower infectivity of HIV-1 upon repeated exposure. First aim will collect human cohort data on sex workers with high-risk behavior as compared to control groups to establish whether their sustained lack of seroconversion is associated with differential levels of cellular innate activation in vivo. Second aim will establish in a non-human primate model whether pre-exposure to defective SIV particles in cervicovaginal compartment (association with pDC recruitment and activation) is associated with a lower transmission rate when animals are challenged with infectious SIV. The proposed study proposed can be considered "high-risk/yield", as once completed it will either prove our hypothesis and open new targets for development of tactics of transmission interruption, or else it will lend further support to concepts on the relationship between inflammation and viral transmission. The research proposed represents a hypothesis-driven multi-disciplinary collaboration between the University of Puerto Rico, The University of Minnesota, The University of Massachusetts, NCI, University of Pennsylvania CFAR, Tulane University and The Wistar Institute.